Potential Cause of Breathing Problems for Rett Syndrome Found

A multi-institutional team, led by University of Chicago researchers, has taken a crucial step toward understanding and treating Rett syndrome (RS), a rare and often-misdiagnosed neurodevelopmental disorder that affects 1 in 10,000 children, mostly females.

In a study published in the Dec. 14, 2005, issue of the Journal of Neuroscience, the researchers describe in a mouse model for RS the source of erratic breathing, which has important implications for children with RS.

Along with breathing problems, RS causes slowed brain and head growth, mental retardation, seizures, gait abnormalities and handwringing.

"It is absolutely tragic for the family," said Jan-Marino Ramirez, professor of organismal biology and anatomy at Chicago and lead author of the paper. "It's a progressive disease that shows no mercy."

In order to study the breathing pattern more closely, Ramirez and his team showed that mice with the RS gene exhibit the same behavior as children: They breathe irregularly and stop breathing often.

According to Ramirez, one hypothesis that has dominated the thinking of many clinicians is that the erratic breathing is due to cortical problems. "It's as if they want to stop breathing," he said. "Some clinicians went that far to suggest that it could be pleasurable for the child to stop breathing all of the time because they get a euphoric high. Or they do this because they're agitated."

However, the researchers traced the problem not to the cortex but to the breathing center itself—in the medulla. The researchers isolated the breathing center from mutant mice and were able to demonstrate that the same erratic breathing pattern, which is so characteristic for RS, also was expressed in the isolated brain tissue, revealing the breathing center as the source of the problem.

They also found, specifically in the breathing center, a significantly decreased amount of the neuromodulator norepinephrine.

When Ramirez's team added norepinephrine to the isolated breathing center, the breathing pattern normalized. "It became exactly as regular as the control— this was amazing," he said. "This experiment shows that the breathing problem can potentially be treated because you can compensate for the missing neuromodulatory drive."

While Ramirez's team worked with the brain tissue, his colleagues in France studied the animal.

Although they found the disturbance specifically in the medulla, many of those neurons project to other targets in the brain, which may explain why many other functions are affected.

Researchers noted that the disturbance in the breathing rhythm of the tissue occurs early on, before the animal exhibits breathing problems. They suggest that the nervous system may compensate initially for the loss of norepinephrine, which may be why breathing appears normal at the behavioral level. However, the deficiency in norepinephrine eventually disturbs other neuromodulators, including serotonin and substance P. As other modulatory systems become disrupted there will be a cascade of physiological problems in the animal's developmental and autonomic systems, including the obvious disturbances in the breathing behavior itself.